Objective: To rationally design, synthesize, and evaluate novel N-(arylidene)-5-(pyridin-4-yl)-1,3,4thiadiazol-2-amines as potential α-amylase inhibitors and antioxidant agents for the treatment of diabetes mellitus. Methods: Molecular docking studies were performed using the Schrödinger Suite 2016-1 against the oligosaccharide-based α-amylase inhibitor target (PDB ID: 1U30). Based on the docking results, seventeen Schiff base derivatives (D1–D17) were synthesized by reacting 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine with various substituted aldehydes. All compounds were characterized by IR, 1H, 13C NMR, and mass spectrometry. The synthesized compounds were evaluated for in vitro antidiabetic activity using the α-amylase inhibition method and for antioxidant activity using the DPPH radical scavenging assay. Results and Discussion: Docking studies revealed that most compounds exhibited good binding affinity, with compounds D2, D3, and D9 showing strong interactions with key active site residues, including HIE201, GLU233, and ASP300. In the α-amylase inhibition assay, compounds D2 and D9 demonstrated the most potent antidiabetic activity, with IC50 values of 26.57 and 29.07 µg/mL, respectively, which were superior to that of the standard drug acarbose (IC50 = 37.41 µg/mL). In the DPPH antioxidant assay, compound D3 exhibited the highest radical scavenging activity, with an IC50 of 12.72 µg/mL, outperforming ascorbic acid (IC50 = 36.61 µg/mL). The strong correlation between molecular docking scores and in vitro biological activity validates the suitability of PDB ID: 1U30 for rational drug design. Compounds bearing electron-donating groups, particularly methoxy and hydroxy substituents (D2, D3, D9), demonstrated enhanced activity due to improved hydrogen bonding interactions with catalytic residues in the α-amylase active site. The ortho-hydroxy group in compound D3 facilitates radical stabilization through resonance, explaining its superior antioxidant potential. These structure–activity relationships confirm that the nature and position of substituents on the arylidene ring critically influence biological activity. Conclusions: The 1,3,4-thiadiazole derivatives D2, D3, and D9 represent promising leads for further in vivo investigation as potential therapeutic agents for managing diabetes and oxidative stress-related conditions. The presence of electron-donating substituents enhances both antidiabetic and antioxidant activities.
Singh et al. (Mon,) studied this question.